Cancer can be defined as an abnormal growth of cells which exhibit signs of uncontrolled proliferation and disturbed programmed cell death. From a classical view, sequential genetic events lead to malignant transformation, resulting in a cell clone that does not respect the integrity of other cells and tissues, and may eventually metastasize. Cancer can involve any tissue of the body and have many different forms in each body area.
Malignant lymphoma can be defined as a malignant transformation of the lymphatic cells of the hematopoietic system. Lymphomas can be divided into aggressive lymphomas and indolent lymphomas. Aggressive lymphomas are characterized by a rapid growth pattern, and can have dramatic clinical features. However, aggressive lymphomas can reach a complete cure by treatment with chemotherapy, radiotherapy and monoclonal antibodies. In contrast, indolent lymphomas (e.g., follicular lymphomas) have a slow growth pattern, and usually a more modest clinical presentation. However, although indolent lymphomas cannot reach a complete cure by standard lymphoma treatment, they can sometimes be cured by allogeneic stem cell transplantation. The median survival time for follicular lymphomas is 8-10 years. Diffuse large B cell lymphoma and Hodgkin lymphoma belong to the group of aggressive lymphomas, while follicular lymphoma and chronic lymphocytic leukaemia are indolent lymphomas. Myelomas consist of malignantly transformed plasmacells. They are related to indolent lymphomas, but are usually considered an entity of their own. The prognosis is pessimistic, with a median survival time of 5-7 years.
Diffuse Large B-cell Lymphoma (DLBCL) is the most frequent subtype of malignant lymphoma, with an incidence of about 500 cases/year in Sweden. DLBCLs constitute 60-70% of the group of aggressive lymphomas. The median age at diagnosis is 70 years, and DLBCL is slightly more common in males than in females. Standard first line treatment of DLBCL is chemotherapy consisting of a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). During recent years addition of the CD20 antibody rituximab has become international clinical standard (R-CHOP), leading to improved progression-free, event-free, disease-free and overall survival (Morrison, Expert Rev Anticancer Ther, 2008; 8(10): pp. 1651-1658). Still, since as many as 45% of patients die from their disease, there is a pronounced clinical need to increase progression-free survival in DLBCL patients.
Regulation of DNA transcription is complex and the mechanisms involved are only partially known. Histone Deacetylases (HDACs) can regulate expression of tumour suppressor genes and activities of transcription factors involved in both cancer initiation and progression. HDACs act through alteration of either DNA or the structural components of chromatin by histone deacetylation, thus affecting the three dimensional conformation of DNA without changing or interrupting its sequence (epigenetic modifications). It has also been suggested that they may alter the sensitivity to DNA damaging chemotherapy through modulation of chromatin structure. Along these lines, several in vitro studies have suggested that HDAC inhibitors can synergize with chemotherapy.
During recent years numerous HDAC inhibitors have been developed. They can be divided into four classes; hydroxamic acids/carbamic acids, cyclic peptides, aliphatic acids and benzamides. For example, vorinostat and romidepsin are approved for the treatment of cutaneous T-cell lymphoma lymphoma by the FDA (Food and drug administration), and are currently evaluated in the treatment of other malignancies.
The clinically most well-known inhibitor is the anticonvulsant valproic acid, which has been utilized in the treatment of epilepsy since the 1970s. Valproic acid belongs to the aliphatic acid class of inhibitors.
EP1 427 403 discloses the use of valproic acid (VPA) and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of human cancer in combination with irradiation treatment wherein the human cancer is selected from the group consisting of breast cancer, colon cancer, head and neck cancer, small cell lung carcinoma and cancer of blood cells. According to EP1602371, VPA could also be used in combinatorial therapy with one or several other anti-cancer treatments which target mechanisms strikingly different from each other such as chemotherapeutic and cytotoxic reagents, differentiation-inducing reagents (e.g. retinoic acid, vitamin D, cytokines), hormonal therapy, immunological approaches and, more recently, the development of anti-angiogenic approaches and gene therapy.
US2008/0194690 discloses the use of an HDAC inhibitor, i.e., certain carbamic acid compounds, such as belinostat (PXD101) in combination with cyclodextrin, arginine or meglumine for the treatment of a number of diseases, including cancer, wherein the solubility of the HDAC inhibitor is enhanced by the addition of one or more of cyclodextrin, arginine or meglumine.